Plasma proteins transport

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

Water-soluble compounds are naturally easily transported in the blood. Non-soluble compounds are usually transported bound to plasma proteins (albumins). This binding is reversible in most cases but may vary remarkably. The degree of protein binding may vary between 50% and 99%. The proportion of the free (unbound) compound in the circulation is the amount of the compound that can reach the tissues and thus the target organs. Very lipid-... 

In addition to secretory cells, many non-secretory cells are capable of regulating exocytotic fusion of transport vesicles that are derived from endosomal precursors. For instance, vesicles enriched in plasma membrane transport proteins are incorporated in a regulated manner in order to alter metabolite fluxes. Examples include the glucose transporter GLUT-4 in muscle and fat tissues, a key element in the control of... 

Plasma protein fractions include human plasma protein fraction 5% and normal serum albumin 5% (Albuminar-5, Buminate 5%) and 25% (Albuminar-25, Buminate 25%). Plasma protein fraction 5% is an IV solution containing 5% human plasma proteins. Serum albumin is obtained from donated whole blood and is a protein found in plasma The albumin fraction of human blood acts to maintain plasma colloid osmotic pressure and as a carrier of intermediate metabolites in the transport and exchange of tissue products. It is critical in regulating the volume of circulating blood. When blood is lost from shock, such as in hemorrhage, there is a reduced plasma volume. When blood volume is reduced, albumin quickly restores the volume in most situations. 

Transferrin (Tf) is a plasma protein that plays a centtal role in transporting iron around the body to sites where... 

The distribution of a drug in the body is largely driven by its physicochemical properties and in part for some compounds by the contribution of transporter proteins [17]. By using the Oie-Tozer equation and estimates for ionization (pfCj). plasma protein binding (PPB) and lipophilicity (log quite robust predictions for the volume of distribution at steady state (Vdss), often within 2-fold of the observed value, can be made [18]. 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

As discussed in the previous section, steroid and thyroid hormones are transported in the blood bound to plasma proteins. The serum concentrations of free hormone (H), plasma protein (P), and bound hormone (HP) are in equilibrium ... 

Steroid and thyroid hormones are minimally soluble in the blood. Binding to plasma proteins renders them water soluble and facilitates their transport. Protein binding also prolongs the circulating half-life of these hormones. Because they are lipid soluble, they cross cell membranes easily. As the blood flows through the kidney, these hormones would enter cells or be... 

The thyroid hormones are lipophilic and relatively insoluble in the plasma. Therefore, they are transported throughout the circulation bound to plasma proteins such as thyroxine-binding globulin (75%) and albumins (25%). Approximately 99.96% of circulating thyroxine is protein bound. Bound hormone is not available to cause any physiological effects however, it is in equilibrium with the remaining 0.04% that is unbound. This free form of the hormone is able to bind to receptors on target tissues and cause its effects. Thyroid hormone has many metabolic effects in the body ... 

Albumin is the most abundant (about 55%) of the plasma proteins. An important function of albumin is to bind with various molecules in the blood and serve as a carrier protein, transporting these substances throughout the circulation. Substances that bind with albumin include hormones amino acids fatty acids bile salts and vitamins. Albumin also serves as an osmotic regulator. Because capillary walls are impermeable to plasma proteins, these molecules exert a powerful osmotic force on water in the blood. In fact, the plasma colloid osmotic pressure exerted by plasma proteins is the only force that retains water within the vascular compartment and therefore maintains blood volume (see Chapter 15). Albumin is synthesized in the liver. 

Figure 12.2 Copper chaperone function, (a) Copper homeostasis in Enterococcus hirae is affected by the proteins encoded by the cop operon. CopA, Cu1+-import ATPase CopB, Cu1+-export ATPase CopY, Cu1+-responsive repressor copZ, chaperone for Cu1+ delivery to CopY. (b) The CTR family of proteins transports copper into yeast cells. Atxlp delivers copper to the CPx-type ATPases located in the post Golgi apparatus for the maturation of Fet3p. (c) Coxl7p delivers copper to the mitochondrial intermembrane space for incorporation into cytochrome c oxidase (CCO). (d) hCTR, a human homologue of CTR, mediates copper-ion uptake into human cells. CCS delivers copper to cytoplasmic Cu/Zn superoxide dismutase (SOD1). Abbreviations IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane PM, plasma membrane PGV, post Golgi vessel. Reprinted from Harrison et al., 2000. Copyright (2000), with permission from Elsevier Science.

Biomarkers of atrazine exposure is a developing field (Lu et al. 1998) that merits additional research. For example, concentrations of atrazine in saliva of rats was significantly correlated with rat free atrazine plasma concentrations. About 26% of the atrazine in rats is bound to plasma proteins (and is unavailable for transport from blood to saliva) and is independent of plasma levels of atrazine. Salivary concentrations of atrazine reflect total plasma free atrazine concentration — in the 50 to 250 pg/L range — which may be of toxicological significance (Lu et al. 1998). 

There have been several studies that underscore the importance of unbound concentration in cell-based studies of receptor function. In a model study of the effect of plasma protein binding on the renal transport of organic anions using the expression of various organic anion transporters (OATPs) in Xenopus oocytes, the transport of ochratoxin A, methotrexate, and estrone sulfate was found to be strongly inhibited by the addition of human serum albumin to the culture medium [16]. Similarly, the addition of oq-acid glycoprotein was found to reverse the blockade of sodium-ion current by cocaine in a preparation of cardiac myocytes [17]. 

Skalsky HL, Farris MW, Blanke RV, et al. 1979. The role of plasma proteins in the transport and distribution of chlordecone (Kepone ) and other polyhalogenated hydrocarbons. In Nicholson WJ, Moore JA, eds. Annals of the New York Academy of Sciences, Health Effects of Halogenated Aromatic Hydrocarbons International Symposium, New York, NY, USA, June 24-27, 1978. New York, NY New York Academy of Sciences, 320 231-237. 

The pulmonary lymphatic system contributes to the clearance of fluid and protein from the lung tissue interstitium and helps to prevent fluid accumulation in the lungs [108], The lymphatic endothelium allows micron-sized particles (e.g. lipoproteins, plasma proteins, bacteria and immune cells) to pass freely into the lymph fluid [103], After administration of aerosolised ultrafine particles into rats, particles were found in the alveolar walls and in pulmonary lymph nodes [135], which suggests that drainage into the lymph may contribute to the air-to-blood transport of the inhaled particles. 

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